Inter-phenylene-ω-aryl-PG amides

ABSTRACT

The present invention relates to inter-phenylene-ω-aryl-PG amides. These compounds are pharmacological agents, being prolonged orally active platelet aggregation inhibitors in mammalian species. These compounds are accordingly useful for antithrombotic applications.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 788,455, filedApr. 18, 1977, now U.S. Pat. No. 4,100,192, issued July 11, 1978.

The present invention relates to inter-phenylene-ω-aryl-PG amides, theessential material constituting a disclosure of which is incorporatedhere by reference from Ser. No. 788,455. In particular, the presentinvention relates to inter-phenylene-ω-aryl-PG amides of theunsubstituted inter-phenylene PG amides described in Ser. No. 788,455now U.S. Pat. No. 4,100,192.

The present invention is particularly concerned with the followingcompounds:

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGF₁α,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF₁α,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-PGD₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGD₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-9,10-didehydro-PGD₁,amide;

3,7-Inter-m-phenylene-3-oxa-15-phenoxy-4,5,6,17,18,19,20-heptanor-PGA₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGE₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-cis-13-PGE₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-PGE₁,amide;

3,7-Inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁, amide;

15-Epi-3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,amide;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE₁,amide;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE₁,amide;

2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGE.sub.1,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-16-methyl-PGE₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-16-methyl-PGE₁,amide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,n-propylamide;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,ethylamide; and

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,methylamide.

I claim:
 1. A prostaglandin analog of the formula ##STR1## wherein R₈ ishydrogen or hydroxy; wherein Y₁ is(1) trans--CH═CH--, or (2)cis--CH═CH--, wherein g is one, 2, or 3; wherein Z₃ is oxa or methylene;wherein L₁ is ##STR2## or a mixture of ##STR3## wherein R₃ and R₄ arehydrogen, methyl, or fluoro, being the same or different, with theproviso that one of R₃ and R₄ is methyl only when the other is hydrogenor methyl; wherein M₁ is ##STR4## wherein R₅ is hydrogen or methyl;wherein R₂₁ and R₂₂ are(i) hydrogen; (ii) alkyl of one to 12 carbonatoms, inclusive; (iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;(iv) aralkyl of 7 to 12 carbon atoms, inclusive; (v) phenyl; (vi) phenylsubstituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms,inclusive, hydroxy or nitro; (vii) hydroxyalkyl of one to 4 carbonatoms, inclusive; (viii) dihydroxyalkyl of one to 4 carbon atoms; or(ix) trihydroxyalkyl of one to 4 carbon atoms;with the further provisothat not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl.wherein Z₄ is

    --(CH.sub.2).sub.h or oxa,

wherein h is zero to 3, inclusive, and wherein s is zero, one, 2, or 3,and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbonatoms, or alkoxy of one to 3 carbon atoms, the various T's being thesame or different, with the proviso that not more than two T's are otherthan alkyl.
 2. A prostaglandin analog according to claim 1, wherein D is##STR5##
 3. A prostaglandin analog according to claim 2, wherein R₈ ishydrogen. 4.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGF₁α,amide, a prostaglandin analog according to claim
 3. 5. A prostaglandinanalog according to claim 2, wherein R₈ is hydroxy. 6.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF.sub.1α,amide, a prostaglandin analog according to claim
 5. 7. A prostaglandinanalog according to claim 1, wherein D is ##STR6##
 8. A prostaglandinanalog according to claim 7, wherein R₈ is hydrogen. 9.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-PGD₁,amide, a prostaglandin analog according to claim
 8. 10. A prostaglandinanalog according to claim 7, wherein R₈ is hydroxy. 11.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGD.sub.1,amide, a prostaglandin analog according to claim
 10. 12. A prostaglandinanalog according to claim 1, wherein D is ##STR7## 13.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-9-deoxy-9,10-didehydro-PGD₁,amide, a prostaglandin analog according to claim
 12. 14. A prostaglandinanalog according to claim 1, wherein ##STR8## 15.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGA.sub.1,amide, a prostaglandin analog according to claim
 14. 16. A prostaglandinanalog according to claim 1, wherein ##STR9##
 17. A prostaglandin analogaccording to claim 16, wherein R₈ is hydrogen. 18.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-PGE.sub.1,amide, a prostaglandin analog according to claim
 17. 19. A prostaglandinanalog according to claim 16, wherein R₈ is hydroxy.
 20. A prostaglandinanalog according to claim 19, wherein Y₁ is cis--CH═CH--. 21.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-cis-13-PGE₁,amide, a prostaglandin analog according to claim
 20. 22. A prostaglandinanalog according to claim 19, wherein Y₁ is --CH₂ CH₂ --. 23.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-PGE₁,amide, a prostaglandin analog according to claim
 22. 24. A prostaglandinanalog according to claim 19, wherein Y₁ is trans--CH═CH--.
 25. Aprostaglandin analog according to claim 24, wherein Z₃ is methylene. 26.A prostaglandin analog according to claim 25, wherein Z₃ is attached tothe phenyl ring in the position meta to methylene. 27.3,7-inter-m-Phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁, amide,a prostaglandin analog according to claim
 26. 28. A prostaglandin analogaccording to claim 24, wherein Z₃ is oxa.
 29. A prostaglandin analogaccording to claim 28, wherein M₁ is ##STR10## 30.15-epi-3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,amide, a prostaglandin analog according to claim
 29. 31. A prostaglandinanalog according to claim 28, wherein M₁ is ##STR11##
 32. Aprostaglandin analog according to claim 31, wherein Z₃ is attached tothe phenyl ring in the position meta to methylene.
 33. A prostaglandinanalog according to claim 32, wherein Z₄ is --(CH₂)_(h). 34.3,7-inter-m-Phenylene-3-oxa-17-phenyl-4,5,6,17,18,19,20-heptanor-PGE₁,amide, a prostaglandin analog according to claim
 33. 35. A prostaglandinanalog according to claim 32, wherein Z₄ is oxa.
 36. A prostaglandinanalog according to claim 32, wherein s is zero or one and T is chloro,fluoro, or trifluoromethyl.
 37. A prostaglandin analog according toclaim 36, wherein g is
 3. 38.2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGE₁,amide, a prostaglandin analog according to claim
 37. 39. A prostaglandinanalog according to claim 36, wherein g is one.
 40. A prostaglandinanalog according to claim 39, wherein at least one of R₃ and R₄ ismethyl. 41.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-16-methyl-PGE₁,amide, a prostaglandin analog according to claim
 49. 42. A prostaglandinanalog according to claim 39, wherein R₃ and R₄ are both hydrogen.
 43. Aprostaglandin analog according to claim 42, wherein R₅ is methyl. 44.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-15-methyl-PGE₁,amide, a prostaglandin analog according to claim
 43. 45. A prostaglandinanalog according to claim 42, wherein R₅ is hydrogen. 46.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,n-propylamide, a prostaglandin analog according to claim
 45. 47.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,ethylamide, a prostaglandin analog according to claim 45.48.3,7-inter-m-Phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGE₁,methylamide, a prostaglandin analog according to claim 45.